The functional role of the activating receptors Tim-3 and CD16 in human natural killer (NK) cell biology

Abstract

Human natural killer (NK) cells are lymphocytes that develop in the bone marrow from hematopoietic progenitor cells (HPCs) and are also found in the lymph nodes, spleen and peripheral blood (PB), where they comprise 10-15% of the mononuclear cell fraction. PB NK cells are phenotypically defined as expressing the surface receptor CD56 (NCAM, neural cell adhesion molecule) and lacking expression of CD3. They mediate their function through the exocytosis of granules that contain lytic enzymes such as perforin and granzymes, the expression of death receptor ligands, the expression of FcRgammaIIIA (CD16, a mediator of antibody-dependent cell-mediated cytotoxicity or ADCC), and the secretion of cytokines and chemokines. As a result, NK cells take part in both the innate and adaptive immune responses and have critical roles in the control of early viral infection, hematopoietic cell transplantation (HCT) and tumor immunosurveillance. The ability of NK cells to differentiate normal healthy cells (self) from infected or transformed (non-self) cells is regulated by a sophisticated repertoire of cell surface receptors that control their activation, proliferation and effector functions. The net balance of inhibitory and activating signals transmitted by these receptors determines whether an NK cell will eliminate its target. The work presented in this manuscript focuses on the modulation of NK cell effector function by two receptors found in their activating repertoire, namely Tim-3 and CD16, and their potential for enhancing the therapeutic effects of NK cells for the treatment of human hematopoietic malignancies.